Orphanin FQ (OFQ), a seventeen amino-acid-long peptide (F-G-G-F-T-G-A-R-K-S-A-R-K-L-A-N-Q), has been isolated from rat brain and is a natural ligand for a G-protein coupled receptor (OFQ-R), found at high levels in brain tissue.
OFQ exhibits agonistic activity at the OFQ-R both in vitro and in vivo.
Julius (Nature 377,476, [1995]) discusses the discovery of OFQ noting that this peptide shares greatest sequence similarity with dynorphin A, an established endogenous ligand for opioid receptors. OFQ inhibits adenylate cyclase in CHO(LC 132.sup.+) cells in culture and induces hyperalgesia when administered intra-cerebroventricularly to mice. The pattern of results indicate that this heptadecapeptide is an endogenous agonist of the LC 132 receptor and it appears to have pro-nociceptive properties. It has been described that when injected intra-cerebroventricularly in mice, OFQ slows down locomotive activity and induces hyperalgesia and it has been concluded that OFQ may act as a brain neurotransmitter to modulate nociceptive and locomotive behavior.
An object of the invention is to provide compounds that are antagonists of the OFQ receptor. Antagonists of the OFQ receptor are useful for treating anxiety and stress disorders, depression, memory loss due to Alzheimer's disease or other dementias, epilepsy and convulsions, acute and/or chronic pain conditions, symptoms of addictive drug withdrawal, control of water balance, Na.sup.+ excretion and arterial blood pressure disorders and metabolic disorders such as obesity.